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© 2002 by the American Diabetes Association, Inc.
Peroxisomal Proliferator-Activated Receptor-
Upregulates Glucokinase Gene Expression in ß-Cells
1 Department of Biochemistry and Molecular Biology, the Institute of Genetic Science, Yonsei University College of Medicine, Seoul, Korea
2 Department of Laboratory Animal Medicine, Medical Research Center, Yonsei, College of Medicine, Seoul, Korea
3 Department of Chemistry, Korea Military Academy, Seoul, Korea
Thiazolidinediones, synthetic ligands of peroxisomal proliferator-activated receptor-
(PPAR-), improve peripheral insulin sensitivity and glucose-stimulated insulin secretion in pancreatic ß-cells. To explore the role of PPAR- in glucose sensing of ß-cells, we have dissected the ß-cell-specific glucokinase (ßGK) promoter, which constitutes glucose-sensing apparatus in pancreatic ß-cells, and identified a peroxisomal proliferator response element (PPRE) in the promoter. The ßGK-PPRE is located in the region between +47 and +68 bp. PPAR-/retinoid X receptor-
heterodimer binds to the element and activates the ßGK promoter. The ßGK promoter lacking or having mutations in PPRE cannot be activated by PPAR-. PPAR- activates the ßGK promoter in ß-cells as well as non-ß-cells. Furthermore, troglitazone increases endogenous GK expression and its enzyme activity in ß-cell lines. These results indicate that PPAR- can regulate GK expression in ß-cells. Taking these results together with our previous work, we conclude that PPAR- regulates gene expression of glucose-sensing apparatus and thereby improves glucose-sensing ability of ß-cells, contributing to the restoration of ß-cell function in type 2 diabetic subjects by troglitazone.
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